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The Discovery of Missing Link Points the Way to Malaria Vaccine

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By Sharon Kingman
Staff Writer

LONDON – The identification of the exact molecule on the insides of blood vessels to which malaria parasites stick will allow an immediate start on work to develop vaccines and new therapies for severe forms of malaria, the scientists who made the discovery predict.

Research published in Nature showed that the malaria parasite, Plasmodium falciparum, binds to a human protein that plays a key role in regulating blood clotting and the response to inflammation.

Thomas Lavstsen, assistant professor at the Centre for Medical Parasitology at the University of Copenhagen, told BioWorld Today: "We have found the receptor to which the parasite proteins bind during the development of severe malaria in children. We have known for a long time that this binding occurs, but until now we have not known the identity of the human protein involved."

That information is critical, he added, to the development of a vaccine that will emulate natural immunity to malaria.

An account of the study is published in the June 5, 2013, issue of Nature, in a paper, titled "Severe malaria is associated with parasite binding to endothelial protein C receptor."

Matthew Higgins, from the University of Oxford, who is a co-author of the paper, said: "Now that we know the pair of proteins involved, we can begin zooming further in to reveal the molecular details of how malaria parasites grab onto the sides of blood vessels. We want to know exactly which bits of the parasite protein are needed to bind to the receptor in the blood vessel wall. Then, we can aim to design vaccines or drugs to prevent this binding."

The malarial parasite invades the red blood cells and displays its own proteins on their surface, which stick to the cells of the vascular endothelium, which line the blood vessels. By staying in the blood vessels, the parasite avoids traveling to the spleen, where it would be eliminated. In one of the most aggressive forms of the disease, the parasite binds to the insides of the blood vessels in the brain, causing cerebral malaria.

According to the World Health Organization, around 600,000 people die from malaria each year, most of them children in Africa. Children are particularly susceptible to malaria but develop immunity as they get older.

In 2012, teams from the University of Copenhagen and Seattle Biomedical Research Institute identified the malarial protein that is involved in binding the parasite-infected red blood cells to blood vessels in cerebral malaria and other severe forms of malaria. That protein is known as PfEMP1.

As described in the current Nature paper, some of the same researchers, collaborating with the biotechnology company Retrogenix Ltd., of Manchester, UK, then embarked on a project to identify the protein to which PfEMP1 binds.

"The first big challenge was to generate a full-length PfEMP1 protein in the laboratory," explained Louise Turner, assistant professor at the University of Copenhagen. "Next, we utilized the technology developed by Retrogenix to examine which of over 2,500 human proteins this PfEMP1 protein could bind to."

The study found that the only "hit" was the human protein called endothelial protein C receptor (EPCR). The normal function of EPCR is to convert protein C into activated protein C (APC), which has many beneficial effects, including damping down inflammation and bringing about anticoagulation.

"When the malarial parasite protein binds EPCR, EPCR can no longer bind to protein C," Lavstsen said. "We believe that the parasite's ability to impair the function of EPCR tends to push some of the reactions to malaria infection towards inflammation, cell death and a higher risk of thrombosis, and that could explain why the symptoms of severe malaria develop."

That knowledge will allow researchers to focus on how the disease progresses at the molecular level, he predicted. "This new understanding of the pathogenesis of severe malaria may shed light on new ways to damp down the harmful effects of the parasite," Lavstsen said.

After the initial finding, Turner said, "a lot of work then went into confirming the binding in the lab, and to show that parasites from non-immune children with severe malaria symptoms in Tanzania often bound EPCR."

Lavstsen said there was "no doubt" that the breakthrough in identifying EPCR was due to the Retrogenix screening tool.

The teams now are going to concentrate on developing a vaccine to prevent severe malaria in children.